CML News/ Blast

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Plant Extract May Block Key Step in Blood Cancer Progression

By , MedPage Today Staff Writer

Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University of

Pennsylvania School of Medicine.

November 14, 2005

MedPage Today Action Points

Advise patients who ask that this study is preliminary and that

treatment of CML with the plant extract forskolin has not been tested in

clinical trials.

Note, however, that the discovery of what appears to be a pathway

leading to the blast crisis stage may open the door to drugs targeting

elements of the pathway.

Review

COLUMBUS, Ohio, Nov. 14 - Geneticists here have identified a key step in

how chronic myelogenous leukemia (CML) transforms from the relatively

indolent chronic phase to the blast crisis -- the final acute stage of

the disease.

In the process, they have also identified what may be a new treatment

for CML -- an extract from the ornamental plant coleus forskohlii, a

member of the mint family found mainly in India.

" We have uncovered a key process that underlies progression in CML and

identified an agent that can block it, " said Perotti, M.D.,

Ph.D., a geneticist at Ohio State's Comprehensive Cancer Center here.

" We believe these are significant findings, " he said. Dr. Perotti and

colleagues reported their discoveries in the November issue of Cancer

Cell.

CML arises when chromosomes 9 and 22 exchange DNA during cell division,

creating a fused gene dubbed BCR-ABL, or the Philadelphia chromosome.

The enzyme produced by the new gene, called Bcr-Abl, kick starts the

growth of new white blood cells, which is the characteristic sign of

CML.

The tyrosine kinase inhibitor Gleevec (imatinib mesylate) blocks

Bcr-Abl, especially if the disease is diagnosed early, although some

patients either fail to respond or progress after initially responding,

Dr. Perotti noted.

As the disease progresses, Dr. Perotti and colleagues found, levels of

BCR-ABL expression increase and the enzyme Bcr-Abl stimulates a

phosphoprotein called SET that is found in the nucleus and cytoplasm of

cells.

SET, in turn, inhibits protein phosphatase 2A (PP2A), an enzyme that is

known to be a tumor suppressor, Dr. Perotti said. PP2A inhibition is

seen in other forms of cancer, but in CML, it's only seen in the blast

crisis.

Remarkably, an extract from the roots of the coleus forskohlii plant --

long used as a treatment for asthma and other illnesses in Hindu

traditional medicine -- is known to restore the activity of PP2A, Dr.

Perotti and colleagues report.

In CML cell lines that were both sensitive and resistant to Gleevec

treatment, the researchers found that the extract, called forskolin,

activated PP2A, reduced the cancer cells' ability to proliferate by 90%,

and induced leukemic differentiation and cell death.

The researchers also found what Dr. Perotti called a " Yin-Yang role of

BCR-ABL and PP2A " -- the gene itself is a target of PP2A, while its

product, Bcr-Abl, acts to inhibit PP2A.

It follows, Dr. Perotti said, that " pharmacologic enhancement of PP2A

tumor suppressor activity may present a novel therapeutic strategy for

blast crisis and Gleevec-resistant CML. "

Indeed, SCID mice injected with cells expressing the BCR-ABL fused gene

lived twice as long if they were treated with forskolin than if they

were not treated at all -- a median of eight weeks, compared with four,

the researchers found.

In a similar experiment, the researchers let forskolin treatment lapse

in using SCID mice that had been injected with BCR-ABL cells and found

-- unexpectedly -- that 20% of them relapsed and died and the remainder

now tested positive for BCR-ABL cells.

But when the drug was restarted, the mice became negative for BCR-ABL

cells and were alive 18 weeks after the experiment started, with no

signs of toxic side effects.

Forskolin, an activator of adenyl cyclase which increases intracellular

cyclic AMP, hasn't been approved by clinical use in the U.S., but it is

widely available as a supplement in health food stores and online. The

antileukemic effects of forskolin, according to the authors, " appear to

depend on induction of PP2A activity rather than increased intracellular

cAMP as exposure of BCR/ABL-transformed cells to the cAMP inducer

theophylline or to a PKA inhibitor in other studies did not alter

BCR/ABL expression/activity. "

Dr. Perotti said forskolin may turn out to be a useful therapy for CML,

but that will depend on the outcome of pre-clinical and clinical trials

that have yet to be conducted.

Primary source: Cancer Cell

Source reference:

Neviani et al. The tumor suppressor PP2A is functionally inactivated in

blast crisis CML through the inhibitory activity of the

BCR/ABL-regulated SET protein. Cancer Cell. 2005; 8:355-68.